Benzamide compounds have been involved as intermediates for the synthesis of many pharmaceutical therapeutic drugs. For example, 2-amino-4,6-dimethoxybenzamide was reported as an intermediate in U.S. Pat. No. 3,966,965 in the synthesis of oxamic acid derivatives for the prevention of hypersensitivity in allergic reactions. More recent patent applications describe this compound as a valuable intermediate en route to new cardiovascular agents (US2008/0188467 and WO2008/92231 to Resverlogix Corp).
2-Amino-4,6-dimethoxybenzamide can be prepared from 4,6-dimethoxyisatoic anhydride. The 4,6-dimethoxyisatoic anhydride may be prepared by a reaction of 4,6-dimethoxyanthranilic acid with phosgene (U.S. Pat. No. 4,191,840 and Org. Synth. 1947, 27, 45). Alternatively, to prepare 2-amino-4,6-dimethoxybenzamide, 3,5-dimethoxyaniline may be converted to its hydrochloride salt, after which the salt is reacted with oxalyl chloride to give 4,6-dimethoxyisatin. The isatin may then be converted to the target compound via an unstable carboxyl intermediate by reaction with sodium hydroxide and hydrogen peroxide followed by an EDCl/HOBt-mediated coupling to form 2-amino-4,6-dimethoxybenzamide (WO2008/92231).
Previously known methods for the synthesis of benzamide compounds and derivatives often involved unstable intermediates, inefficient processes, and in some cases, a large number of steps, resulting in lower yields and increased costs of manufacturing. Thus, there is a continuing need for methods to make benzamide compounds and derivatives that are efficient, do not require the use of exotic or unstable reagents, use low-cost reagents, and provide environmentally streamlined processes.